Circulating T-cell receptor repertoire for cancer early detection
npj Precision Oncology, 2025
Li Y., Nahas M., Stephens D., Froburg K., Hintz E., Champagne D., Lochab A., Brown M., Braun J., Fortuño M., Ocón M., Pasquier A., Luque-Vázquez I., Moudgalya H., Kivlehan S., Gjeci I., Korle S., Campo A., Rodriguez M., Seder C., Lizotte P., Bueno R., Borgia J., Seijo L., Montuenga L., Yelensky R.
Disease area | Application area | Sample type | Products |
---|---|---|---|
Oncology | Patient Stratification | Plasma | Olink Explore 3072/384 |
Abstract
Liquid biopsy is a promising non-invasive technology that is capable of diagnosing cancer. However, current ctDNA-based approaches detect only a minority of early-stage disease. We set out to improve the sensitivity of liquid biopsy by harnessing tumor recognition by T cells through the sequencing of the circulating T-cell receptor repertoire. We studied a cohort of 463 patients with lung cancer (86% stage I) and 587 subjects without cancer using gDNA extracted from blood buffy coats. We performed TCR β chain sequencing to yield a median of 113,571 TCR clonotypes per sample and built a TCR sequence similarity graph to cluster clonotypes into TCR repertoire functional units (RFUs). The TCR frequencies of RFUs were tested for association with cancer status and RFUs with a statistically significant association were combined into a cancer score using a support vector machine model. The model was evaluated by 10-fold cross-validation and compared with a ctDNA panel of 237 mutation hotspots in 154 lung cancer driver genes and 17 cancer related protein biomarkers in 85 subjects. We identified 327 cancer-associated TCR RFUs with a false discovery rate (FDR) ≤ 0.1, including 157 enriched in cancer samples and 170 enriched in controls. Levels of 247/327 (76%) RFUs were correlated with the presence of an HLA allele at FDR ≤ 0.1 and tumor-infiltrating lymphocyte TCRs from multiple RFUs bound HLA presented tumor antigen peptides, suggesting antigen recognition as a driver of the cancer-RFU associations found. The RFU cancer score detected nearly 50% of stage I lung cancers at a specificity of 80% and boosted the sensitivity by up to 20 percentage points when added to ctDNA and circulating proteins in a multi-analyte cancer screening test. Overall, we show that circulating TCR repertoire functional unit analysis can complement established analytes to improve liquid biopsy sensitivity for early-stage cancer.